Process for the enatioselective synthesis of intermediates used

ABSTRACT

A process for the stereoselective synthesis of  R!- and  S!-2,3-dihydro-1,3-dimethyl-2-oxo-1H-indole-3-acetonitriles comprises reacting racemic and 5-alkoxy-substituted (±)-1,3-dimethyloxindoles with a halogenated acetonitrile in the presence of a substituted N-benzyl cinchoninium, quinidinium, cinchonidinium, or quininium catalyst. The resulting alkylated oxindoles can be converted to primary amines by catalytic reduction in the presence of hydrogen gas. One of the primary amines, such as enantiomers of 3-(2-aminoethyl)-1,3-dihydro-1,3-dimethyl-5-methoxy-2H-indol-2-one, can be enriched by contact with a chiral tartaric acid in an amount sufficient to preferentially precipitate a salt of the chiral acid and one of the enantiomers. The product can be used in the synthesis of stereospecific forms of physostigmine and related compounds having pharmaceutical activity.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation of application Ser. No. 08/463,144, filed Jun. 5,1995, now abandoned which is a division of application Ser. No.08/067,892, filed May 27, 1993, now issued U.S. Pat. No. 5,521,320;which is a CIP of application Ser. No. 07/833,608, filed Feb. 12, 1992,now issued U.S. Pat. No. 5,274,117; which is a continuation ofapplication Ser. No. 07/640,514, filed Jan. 3, 1991, now abandoned;which is a continuation of application Ser. No. 07/469,882, filed Jan.22, 1990, now abandoned--which is herein incorporated by reference.

BACKGROUND OF THE INVENTION

This invention relates to a process for the selective synthesis ofstereoisomers. More particularly, this invention relates to a processfor the stereoselective synthesis of enantiomers of nitriles and primaryamines that are useful in the synthesis of (+)-physostigmine and(-)-physostigmine.

The cholinergic neuronal system can be found in the central nervoussystem (CNS), in the autonomic nervous system, and in the skeletal motorsystem. Acetylcholine (ACh) is the neurotransmitter in all ganglia, theneuromuscular junction, and the post-ganglionic synapses of thecholinergic nervous system. Acetylcholine is normally an excitatoryneurotransmitter that binds to nicotinic and muscarinic receptors.

Acetylcholinesterase (AChE) is an enzyme that hydrolyzes and therebydeactivates ACh after it binds to a receptor. This enzyme is present inall peripheral and central junctional sites and in certain cells of thebody.

In some circumstances, it is desirable to stimulate acetylcholinereceptors. One method involves the use of indirect agonists, such asanticholinesterase drugs, which inhibit the hydrolysis of ACh by AChE.When an anticholinesterase drug blocks AChE and inhibits the destructionof released ACh, a higher neurotransmitter level and increasedbiological response result. The alkaloid, physostigmine, which can beisolated from the seeds of the Calabar bean, has been found to beparticularly effective as an anticholinesterase drug. Physostigmine hasa high affinity for AChE and is capable of inhibiting AChE for prolongedperiods.

It is believed that degeneration of the cholinergic pathways in the CNSand the resultant development of apparent irregularities in neuronarrangement may be a principal cause of senile dementia of the Alzheimertype. This disease leads to progressive regression of memory and learnedfunctions. Since the average age of the population is on the increase,the frequency of Alzheimer's disease is increasing and requires urgentattention.

It has been suggested that cholinergic agonists, such as theanticholinesterase drugs, are useful in the treatment of Alzheimer'sdisease. Nevertheless, drug treatment with anticholinesterase drugs hasnot proved entirely satisfactory. Thus, there is a need in the art fornew forms of drugs for the treatment of this disease.

The enantiomers of physostigmine and pharmaceutically activephysostigmine-like compounds, such as the compounds described in U.S.Pat. No. 4,791,107, are under investigation for the treatment ofAlzheimer's disease. In order to satisfy the need for compounds havingthe highest pharmaceutical activity, there exists a need in the art fora process for the stereoselective synthesis of the enantiomers.Specifically, the enantiomer (-)physostigmine is of current interest,and while methods for preparing physostigmine and physostigmine-likecompounds have been proposed, there exists a need in the art for astereoselective process for producing the S- or (-)-forms.

It has been found that the compound1,3-dimethyl-5-methoxyoxindolylethylamine, also referred to as3-(2-aminoethyl)-1,3-dihydro-1,3-dimethyl-5-methoxy-2H-indol-2-one, isan important intermediate in a recently discovered method ofsynthesizing (-)-physostigmine. While this amine can be prepared usingconventional techniques, a racemic mixture is usually formed. Resolutionof the racemic amine mixture into its R and S components makes itpossible to synthesize (+)-physostigmine and (-)-physostigmine.

A process for the stereoselective synthesis of the amines and theirprecursors could provide certain advantages. Such a process could reduceor eliminate the need for resolving mixtures of enantiomers. Whilestereoselective syntheses that are catalyzed by enzymes are highlyenantioselective, non-enzymatic processes have a wide range ofselectivity. Accordingly, the results obtained in processes based onsynthetic chemical techniques are generally unpredictable, andsuccessful results in stereoselective syntheses have been difficult toachieve.

Thus, there exists a need in the art for methods based on chemicaltechniques for producing enantiomers of physostigmine andphysostigmine-like compounds. There also exists a need in the art formethods for the asymmetric synthesis of intermediates for use in theprocess. The method should make it possible to obtain the intermediatesin a state of high optical purity. In addition, the process should beeasy to carry out and should employ reagents that are readily available.

SUMMARY OF THE INVENTION

Accordingly, this invention aids in fulfilling these needs in the art byproviding a process for the stereoselective synthesis of an oxindole,wherein the process comprises reacting a racemic oxindole of the formula##STR1## where R is selected from the group consisting of methyl, ethyl,and benzyl, with at least one equivalent of a halogenated acetonitrileselected from the group consisting of chloroacetonitrile,bromoacetonitrile, and iodoacetonitrile. The reaction is carried out ina biphasic reaction mixture having an aqueous phase comprising a stronginorganic base as a deprotonation agent, and a solvent phase comprisingan organic solvent for the oxindole. The biphasic reaction mixtureincludes a catalytic amount of a substituted N-benzyl cinchoninium orquinidinium compound of the formula ##STR2## or a substituted N-benzylcinchonidinium or quininium compound of the formula ##STR3## where R₁ isa vinyl group or an ethyl group,

R₂ is hydrogen or a methoxy group,

X is chlorine or bromine,

Y is independently selected from the group consisting of hydrogen,chlorine, bromine, fluorine, trifluoromethyl groups, and nitrile groups;and

n is 1, 2, 3, 4, and 5.

The 5-alkoxy-2,3-dihydro-1,3-dimethyl-2-oxo-1H-indole-3-acetonitrilesthat are formed in the process of this invention can be further reducedto their corresponding amines which can be used in the synthesis ofstereospecific forms of physostigmine and physostigmine-like compounds.In particular, the S-form of 1,3-dimethyl-5-methoxyoxindolyl-ethylamineis useful for preparing (-)-physostigmine.

BRIEF DESCRIPTION OF THE DRAWING

This invention will be more fully understood by reference to thedrawing, which depicts a reaction scheme for the asymmetric synthesis ofalkylated oxindoles 2a and 2b and conversion of these compounds toprimary amines 3a and 3b. The primary amines are useful in thepreparation of enantiomers of physostigmine and physostigmine-likecompounds having pharmaceutical activity.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The asymmetric synthesis of the present invention involves conversion ofan achiral substrate to a chiral product using a chiral reagent. Aprochiral function serves as the precursor for a chiral product duringthe reaction. The following nomenclature and conventions are employed indescribing this invention.

As used herein, the expression "asymmetric synthesis" means a synthesisin which an asymmetric atom, instead of being in a molecule before thecommencement of the synthesis, is introduced into the molecule in thecourse of chemical reaction. Thus, for example, the asymmetric synthesisof the present invention is a reaction in which an achiral unit in asubstrate molecule is converted by a chiral reagent into a chiral unitin such a manner that the stereoisomeric products are produced inunequal amounts.

The expression "enantioselective synthesis" means a synthesis thatproduces one enantiomer of a given structure in considerablepredominance over the other possible enantiomer. The enantioselectivesynthesis of the present invention typically produces the predominantenantiomer in an amount of about 70% to about 90%, usually about 85% toabout 88%, of the total enantiomers formed as products of the synthesis.

As used herein, the expressions "enantiomeric mixture" and "mixture ofenantiomers" are used interchangeably to refer to racemic modificationsof the enantiomers. The expressions also include solutions containingboth of the enantiomers, wherein the solutions exhibit either (+) or (-)optical rotation as observed and measured with a polarimeter.

The terms "resolve" and "resolution" as used herein are intended toencompass the complete or partial separation of two enantiomers of5-alkoxy-substituted 1,3-dimethylindolylethylamines, also referred to as5-alkoxysubstituted-3-(2-aminoethyl)-1,3-dihydro-1,3-dimethyl-2H-indol-2-one.The separation is described in more detail hereinafter. These two termsare intended to cover separations in which only one of the enantiomersis obtained in a pure state. The terms are also intended to encompasssome degree of separation of the enantiomers, wherein neither of theenantiomers is obtained completely free of the other. Separation of theenantiomers may or may not be quantitative.

The heavy line in the form of a wedge in the formulas herein signifiesthat the substituents are above the average plane of the ring system inconnection with which the wedge appears. The heavy broken lines in theform of a wedge signify that the substituents are below the averageplane of the ring system. For example, in the formula for one of theprimary amines produced according to this invention, the methyl group inthe 3-position is above the average plane of the oxindole ring, whereasthe aminoethyl group is below the average plane of the ring. Thus, themethyl group and the aminoethyl group are trans to each other relativeto the average plane of the ring.

The stereoselective synthesis of the invention can be carried out asshown in the Figure. Referring to the Figure, an oxindole 1 can bealkylated with a halogenated acetonitrile in the presence of a chiralcatalyst to give an enantiomeric mixture comprising alkylated oxindoles2a and 2b, which are terms R!- andS!-5-alkoxy-2,3-dihydro-1,3-dimethyl-2-oxo-1H-indole-3-acetonitrile. Itwas surprisingly discovered that one of the alkylated oxindolespredominates in the reaction product. In addition, it was unexpectedlyfound that the alkylated oxindoles 2a and 2b are obtained in relativelyhigh chemical yield.

The crude enantiomeric mixture comprising the alkylated oxindoles 2a and2b can be hydrogenated in the presence of a catalyst to form a mixturecomprising primary amines 3a and 3b, which are terms R!- andS!-5-alkoxy-3-(2-aminoethyl)-1,3-dihydro-1,3-dimethyl-2H-indol-2-ones.The primary amine 3a in which R is a methyl group is an importantintermediate in the preparation of (-)-physostigmine.

The primary amine should be available in as pure a form of the opticalisomer as possible in order to obtain high yields and optical purity ofphysostigmine and physostigmine-like compounds. This can be achieved byselectively precipitating the enantiomer 3a or 3b with a chiral tartaricacid to form a tartaric acid salt 4a or 4b. One method of preparing theenantiomeric mixture 3a and 3b will now be described in greater detail.

The asymmetric synthesis of the present invention is carried out by thestereoselective alkylation of an oxindole of the formula: ##STR4##wherein the substituent R is selected from the group consisting ofmethyl (compound (1a)), ethyl (compound (1b)), and benzyl (compound(1c)). The oxindole 1 is a racemic mixture. The oxindole 1 is employedin the process of this invention as a racemic mixture, which can beprepared by the synthetic methods disclosed in Julian et al., J. Chem.Soc., 57:563-566 and 755-757 (1935) and in U.S. Pat. No. 4,791,107.

The oxindole 1 can be selectively converted to an enantiomeric mixturecomprising alkylated oxindoles 2a and 2b using a chiral phase transfercatalyst. Examples of suitable catalysts are those derived fromsubstituted N-benzyl cinchoninium or quinidinium or N-benzylchinconidinium or quininium halides. The reaction is characterized byhigh enantioselectivity.

More particularly, the stereoselective conversion of oxindole 1 to anenantiomeric mixture comprising the alkylated oxindoles 2a and 2b can becarried out by stirring a racemic mixture of the oxindole 1 and a chiralcatalyst in a two-phase system comprised of a strong inorganic base andan organic solvent under an inert gas atmosphere until the reaction goesto substantial completion. Chemical conversion can be monitored byanalyzing the reaction mixture by GLC for the formation of the alkylatedoxindoles 2a and 2b. The enantiomer 2a or 2b that predominates isdependent upon the nature of the chiral catalyst that is employed.

The chiral catalyst for the selective conversion of oxindole 1 to thealkylated oxindole 2a or 2b is a substituted N-benzyl cinchoninium orquinidinium compound of the formula ##STR5## or a substituted N-benzylcinchonidinium or quininium compound of the formula ##STR6## where R₁ isa vinyl group of an ethyl group,

R₂ is hydrogen or a methoxy group,

X is chlorine or bromine,

Y is independently selected from hydrogen, chlorine, bromine, fluorine,trifluoromethyl groups, and nitrile groups; and

n is 1, 2, 3, 4 or 5.

The substituted N-benzyl cinchoninium and the substituted N-benzylquinidinium compounds have the formula (I) in which R₂ is hydrogen ormethoxy, respectively. The substituted N-benzyl cinchonidinium and thesubstituted N-benzyl quininium compounds have the formula (II) in whichR₂ is hydrogen or methoxy, respectively. The preferred catalysts arecompounds in which Y is 3,4-dichloro or 4-trifluoromethyl. Thesecatalysts can be prepared by utilising the procedures described in J.Ong. Chem. 1987, 52, 4745-4752 and are commercially available from FlukaChemical Co., Hanppauge, N.Y. 11788, or from Chemical DynamicsCorporation of South Plainfield, N.J.

The substituted N-benzyl cinchoninium and quinidinium compounds and thesubstituted N-benzyl cinchonidinium and quininium compounds are employedin the asymmetric synthesis of the invention in an amount sufficient tocatalyze the reaction of the oxindole and the halogenated acetonitrileto produce one of the enantiomers of the alkylated oxindoles in apredominant amount over the other enantiomer. For example, the catalystcan be employed in an amount of about 5 to about 50 mole % based uponthe amount of oxindole 1. In a preferred embodiment of this invention,the compounds are employed as catalysts in an amount of about 10 toabout 15 mole % based upon oxindole 1.

The substituted N-benzyl cinchoninium and quinidinium compounds providethe alkylated oxindole 2a in excess while the substituted N-benzylcinchonidinium and quininium compounds yield the alkylated oxindole 2bin excess when the compounds are used in a catalytically effectiveamount. It will be understood that the asymmetric synthesis of thisinvention can also be carried out in the presence of a surfactant, suchas Triton X-400. See U.S. Pat. Nos. 4,578,509 and 4,605,761.

Alkylation of the oxindole appears to proceed by conventionalmechanisms. For this reason it was anticipated that a racemic mixture ofthe alkylated oxindoles would be obtained. Quite unexpectedly, however,it was found that the alkylation reaction was stereoselective and thateither one of the enantiomers of the alkylated oxindoles can be obtainedin excess, depending upon the choice of catalyst. Moreover, thepredominant enantiomer is obtained in high chemical yield. The chemicalyield is at least about 60% based on oxindole 1, and is generally about65% to about 85% based on oxindole 1.

The stereoselective synthesis of this invention is carried out in abiphasic reaction mixture comprised of an organic solvent phasecontaining the racemic mixture of oxindole 1 and the catalyst and anaqueous phase containing a strong inorganic base. The oxindole 1 and thecatalyst are dissolved in an aromatic hydrocarbon solvent. Halogenatedaromatic solvents and halogenated aliphatic solvents can also beemployed. Typical of the solvents that can be utilized are benzene,toluene, xylene, chlorobenzene, and methylene chloride. Solvent mixturesof hexane and cyclohexane can also be utilized. Technical grade solventshave been found to yield acceptable results. The preferred solvent istoluene because reaction mixtures containing this solvent gave thehighest selectively of the alkylated oxindole 2a or 2b in the exampleshereinafter. The selectivity obtained with other solvents can beoptimized with a minimum of experimentation.

The aqueous phase of the reaction mixture contains a strong inorganicbase, such as potassium hydroxide, sodium hydroxide, or lithiumhydroxide. Technical grade bases have been found to produce acceptableresults. The preferred base is sodium hydroxide because of its low cost,availability, and effectiveness in the process of the invention.

The inorganic base is employed in an amount sufficient to supportcatalysis of the reaction. The base functions as a deprotonation agent.It has been found that the concentration of the base in the aqueousphase affects the selectivity. The concentration of base in the aqueousphase is typically about 25% to about 50% by weight. As theconcentration of base decreases, the selectivity for one of thealkylated oxindole decreases.

The aqueous phase containing the inorganic base should have minimumsolubility in the organic solvent phase containing the racemic oxindole1 and the catalyst in order to maintain a biphasic reaction mixture. Thevolume ratio of the organic phase of the reaction mixture to the aqueousphase is typically about 3:1 to about 10:1. A reaction mixturecontaining the organic phase and the aqueous phase in a volume ratio ofabout 5:1 has been found to produce favorable results.

The organic solvent phase and the oxindole 1 in the reaction mixture isgenerally about 20:1 to about 80:1, preferably about 30:1 to about 45:1.The particularly preferred ratio is about 40:1. These ratios areexpressed as the volume of the organic solvent phase to the weight ofthe oxindole 1.

The alkylating agent for the racemic mixture of oxindole 1 can be ahalogenated acetonitrile selected from the group consisting ofchloroacetonitrile, bromoacetonitrile, and iodoacetonitrile.Chloroacetonitrile is the preferred alkylating agent because it hasprovided the highest selectivity of the alkylated oxindoles 2a and 2b.Technical grade alkylating agents have yielded satisfactory results.

The halogenated acetonitrile is employed in an amount of at least aboutone equivalent, and preferably about 1.1 to about 1.5 equivalents, ofthe racemic mixture of oxindole 1. Increasing the amount of thealkylating agent relative to the oxindole generally increases chemicalyield, although there is no apparent advantage in utilizing thealkylating agent in large excess.

The stereoselective synthesis of the invention is generally carried outat a temperature of about 5° C. to about 30° C. Lower temperatures aregenerally accompanied by higher selectivity of the alkylated oxindole 2aor 2b, although caution must be exercised to avoid the inorganic basefrom separating from the aqueous solution at low temperatures. Thepreferred temperature range for carrying out the synthesis is about 15°C. to about 25° C., especially about 20° C.

The stereoselective synthesis of the alkylated oxindole 2a or 2b is anexothermic reaction. The reaction mixture can be cooled by internal orexternal means to maintain the reaction temperature. The need forcooling can be minimized and even avoided by gradually adding thehalogenated acetonitrile to the biphasic reaction mixture.

It is desirable to provide an inert gas blanket over the biphasicreaction mixture in which the asymmetric synthesis is carried out inorder to exclude oxygen from the reaction. Examples of suitable inertgases include nitrogen, argon, and helium. Nitrogen is preferred foreconomic reasons.

The stereoselective synthesis of the invention can be carried out atatmospheric pressure. Sub-atmospheric pressures should be avoided.

It has been found that alkylation of the racemic mixture of oxindole 1proceeds very rapidly. With gradual addition of the alkylating agent tothe biphasic reaction mixture, the reaction is generally complete withinabout 1 to about 2 hours. Shorter reaction times can be employed,although cooling of the reaction mixture may be required. Similarly,longer reaction periods can be utilized, although there is no apparentadvantage in extending the reaction time. In any event, the alkylatingreaction is carried to substantial completion, which can be monitored bygas chromatography or other suitable means. In order to optimizeselectivity for the alkylated oxindole 2a or 2b, the reaction mixtureshould be agitated.

The biphasic reaction mixture can be prepared as follows. The racemicmixture of oxindole 1 can be dissolved in the organic solvent and thecatalyst can be added to the resulting solution. The aqueous solution ofthe inorganic base can then be added to the organic solution and stirredfor a sufficient period to form the biphasic reaction mixture. Mildstirring for about 10 minutes has been found to be sufficient to formthe biphasic mixture. The halogenated acetonitrile employed as thealkylating agent can then be added to the biphasic reaction mixture.Slow addition of the alkylating agent improves selectivity for thepredominating alkylated oxindole 2a or 2b.

The optical purity of the enantiomers formed in the process of thisinvention can be expressed as the excess of the enantiomer in thereaction produce as a percentage of the total enantiomers in theoriginal solution. The amount of an enantiomer is conveniently expressedas the percent enantiomeric excess, which is abbreviated "% ee". Thepercent enantiomeric excess can be calculated as follows: ##EQU1## whereA! is the concentration of one of the enantiomers, and B! is theconcentration of the other enantiomer. In a completely resolvedmaterial, the enantiomeric excess is equal in weight to the totalmaterial so that % ee, and thus optical purity, is 100%. Theconcentration of each of the enantiomers is, of course, expressed on thesame basis, and can be expressed on either a weight of molar basisbecause the enantiomers have the same molecular weight.

A number of substituted N-benzyl cinchoninium salts have been screenedfor selective conversion of oxindole 1 to alkylated oxindole 2a. All thereactions were carried out by stirring a mixture of oxindole 1 (2.5mmol) and the appropriate catalyst (0.25 mmol) in a two-phase systemconsisting of 8 ml of 50% NaOH and 20 ml of toluene under nitrogen for10 min. A solution of chloroacetonitrile (2.75 mmol) in 20 ml of toluenewas then added via a syringe pump over a period of 1 hour. Aftercompletion addition, the reaction mixture was analyzed by GLC forchemical conversion. Enantiomeric excess of alkylated oxindole 2a wasdetermined by HPLC on a Chiralcel OD column or a Chiracel OJ column(Daicel Chemical Industries Ltd.) and by NMR spectroscopy using tris3-(heptafluoropropyl-hydroxymethylene)-d-camphorato!europium (III) asthe chiral shift reagent. The results are summarized in Table I.

                  TABLE I                                                         ______________________________________                                        Asymmetric Alkylation of Oxindole 1                                           Using Chiral Phase Transfer Catalysts.                                         ##STR7##                                                                            Catalysts                                                              Expts.   R.sub.1 R.sub.2  Y        X   % ee 2a                                ______________________________________                                         1       vinyl   H        H        Cl  >3                                      2       vinyl   H        H        Br  10                                      3       vinyl   H        2-F      Br   5                                      4       vinyl   H        2-CF.sub.3                                                                             Br   4                                      5       vinyl   H        2,6-Cl.sub.2                                                                           Br  >3                                      6       vinyl   H        3-F      Br   8                                      7       vinyl   H        3-Br     Br  48                                      8       vinyl   H        4-Br     Br  68                                      9       vinyl   H        4-CF.sub.3 *                                                                           Br  72                                     10       vinyl   H        4-CN     Br  >2                                     11       vinyl   H        3,4-Cl.sub.2                                                                           Cl  78                                     12       vinyl   H        3,4-Cl.sub.2                                                                           Br  77                                     13**     vinyl   H        3,4-Cl.sub.2 ***                                                                       Cl  17                                     14****   vinyl   H        4-CF.sub.3                                                                             Br  61                                     15       Et      H        4-CF.sub.3                                                                             Br  69                                     16       vinyl   OCH.sub.3                                                                              H        Br  39                                     17       vinyl   OCH.sub.3                                                                              3,4-Cl.sub.2                                                                           Br  77                                     ______________________________________                                         *4-CF.sub.3 BCMB                                                              **1:1 toluene/hexanes                                                         ***3,4Cl.sub.2 -BCMC                                                          ****25% NaOH                                                             

Substitution in the 3 and/or 4 position of the benzyl moiety of thecatalyst with electron withdrawing groups, such as Br, Cl, or CF₃,significantly increased the %ee of alkylated oxindole 2a, (Expts. 7, 8,9, and 12). This is probably due to a tighter ion-pair being formed as aresult of increased positive character on the N-atom of the cinchoniniumcatalyst. That the observed enhancement of % ee by electron withdrawinggroups is mainly due to inductive effect and not resonance effect issuggested by the low % ee observed for the 4-cyanobenzylcinchoniniumbromide, (Expt. 10). The fluoro-substituted catalysts gave unexpectedlylow % ee for reasons not yet identified, (Experiments 3 and 6). Asexpected, the dihydrocinchoninium catalyst behaved similarly to thecorresponding cinchoninium salt, (Experiments 9 and 15). Unexpectedly, amoderate % ee was observed with benzylquinidinium bromide, (Experiment16). No further improvement in % ee was observed when the benzyl groupwas further substituted with an electron withdrawing group, (Experiment17). A slight counterion effect was observed for the case where the % eeof the reaction was low, (Experiments 1 and 2). When the % ee of thereaction was appreciably high, counterion effect was nonexistent.

It is generally not possible to separate predominant alkylated oxindolefrom the other oxindole formed in the stereoselective synthesis of theinvention. Therefore, the crude mixture containing the alkylatedoxindole is employed in the next step of the reaction, which involvesthe conversion of the nitrile groups of the alkylated oxindoles to thecorresponding primary amines via catalytic reduction in the presence ofhydrogen gas. This step of the reaction can be carried out usingconventional techniques. For example, the crude reaction product fromthe stereoselective synthesis can be taken up in a suitable solvent,such as methanol, ethanol, or 2-propanol. The resulting solution can behydrogenated in the presence of a catalytic amount of metallic catalyst,such as PtO₂ or platinum on carbon, in an aqueous, alcoholic,concentrated HCl medium or in acetic acid as solvent to form a mixturecomprising primary amines 3a and 3b. The catalyst is typically employedin an amount of about 5% to about 50% by weight. The reaction carriedout at a temperature of about 15° C. to about 30° C. for about 1 hour toabout 2 hours until the reaction proceeds to substantial completion.Acids, such as sulfuric acid, phosphoric acid, and hydrobromic acid, canbe employed in place of HCl. The % ee of the primary amines are formedin approximately the same relative proportion as that of the oxindolesat the start of the catalytic reduction of the nitrile.

The % ee of the primary amines 3a and 3b in the enantiomeric mixturefrom the reduction reaction can be further improved by resolution withan optically active derivative of tartaric acid. Different solubilitycharacteristics of the diastereomeric salts make it possible topreferentially isolate one of the salts. More particularly, a reactionmixture containing both of the enantiomers of the primary amine insolution is allowed to interact with an optically active derivative oftartaric acid to form a salt, which readily forms a precipitate in thereaction mixture. The enantiomer in an optically purified state can berecovered from the precipitate by treatment with a mineral base.

More particularly, the enantiomers of the primary amines can be resolvedwith a chiral acid selected from the group consisting ofdibenzoyl-D-tartaric acid, dibenzoyl-L-tartaric acid, ditoluoylD-tartaric acid, or ditoluoyl-L-tartaric acid. The preferred chiral acidis dibenzoyl-D-tartaric acid, because the S-enantiomer of1,3-dimethyl-5-methoxyoxindolylethylamine can be selectivelyprecipitated from an enantiomeric mixture with this acid in relativelyhigh optical purity. It is preferred that the chiral acid be in asubstantially optically pure state. The D-form of the chiral acid can beemployed to preferentially precipitate enantiomer 3a, while the L-formof the chiral acid can be employed to preferentially precipitate theenantiomer 3b.

The amount of the chiral acid employed in the enrichment process willgenerally be about 0.5 to about 1 equivalent of acid per equivalent ofthe primary amine, and preferably about 0.6 to about 0.9 equivalent. Ithas been found that the amount of the chiral acid used as the resolvingagent can affect the identity of the enantiomer of the primary aminethat is preferentially precipitated. For example, when the racemic amine3a and 3b is treated with one or more equivalents ofdibenzoyl-D-tartaric acid in an appropriate solvent, such asacetonitrile, the diastereomeric salt corresponding to the R-enantiomer3b is preferentially precipitated. On the other hand, when less than 1equivalent of dibenzoyl-D-tartaric acid is employed, the diastereomericsalt corresponding to the S-enantiomer 3a is preferentiallyprecipitated. In the preferred method of carrying out the enrichmentprocess of the invention, the enantiomer 3a is preferentiallyprecipitated from a racemic mixture of 3a and 3b withdibenzoyl-D-tartaric acid in an amount of about 0.6 to about 0.9equivalent of the acid per equivalent of the primary amine.

The enrichment process is carried out in a solution comprising theenantiomers and the chiral acid. The solution is prepared with anorganic solvent in which the enantiomers and the chiral acid aresoluble, but in which one of the tartaric acid salts of the enantiomersis less soluble so that one of the salts of the enantiomers willpreferentially precipitate. The solvent is typically a liquid organiccompound, such as cyclic or acyclic substituted hydrocarbon. Ethers,such as diethyl ether, dioxane, and tetrahydrofuran, can be employed.Examples of suitable halogenated solvents are methylene chloride andchloroform. The organic compound can be an aromatic compound, such astoluene of xylene. Aliphatic nitriles, such as acetonitrile andpropionitrile, can also be employed. The preferred solvent isacetonitrile.

The ratio of the solvent volume to the amount of enantiomers in themixture being resolved can be varied over a relatively broad range. Theratio of the amount of solvent to the amount of enantiomers cantypically be about 5:1 to about 15:1, where the ratio is expressed asthe volume of solvent relative to the weight of the enantiomers in thesolvent. Preferably the ratio is about 8:1 to about 12:1. In a preferredprocess of carrying out this invention, the ratio of the volume ofsolvent to the weight of enantiomers is about 10:1.

The solution containing the enantiomers can be prepared by dissolvingthe enantiomeric mixture in the solvent. Dissolution can typically becarried out at a temperature of about 0° C. to about 60° C., but willgenerally be carried out at room temperature of about 18° C. to about22° C. Similarly, the chiral acid can be dissolved in a solvent, whichis generally the same solvent as the solvent employed for theenantiomeric mixture.

After the resolving agent is added to the solution of the enantiomers,the resulting solution is aged under conditions to form a precipitatecomprising a salt of the chiral acid and the enantiomer that isselectively precipitated. Aging is typically carried out at atemperature of about 0° C. to about 30° C. The use of temperatureswithin the lower end of this range will generally facilitate theformation of precipitates and increase the yield because the salts aregenerally less soluble in the solvent at the lower temperatures. On theother hand, the use of temperatures within the upper end of this rangewill generally provide higher selectivity; that is, formation of one ofthe salts of the enantiomers will be favored over the other salt.

Resolution of the enantiomeric mixture of the primary amines accordingto this invention provides a precipitate of one of the enantiomers inthe form of a salt of tartaric acid. The tartaric acid salt can beconverted to the corresponding free base by conventional techniques. Forexample, the tartaric acid salt can be dissolved in water, and theresulting solution can be treated with an aqueous solution comprised ofa non-toxic inorganic base in an amount sufficient to provide asubstantially basic mixture. Examples of suitable bases include sodiumhydroxide, potassium hydroxide, sodium carbonate, and potassiumcarbonate. The amine is extracted with an organic solvent from theaqueous solution. An organic solvent, such as methylene chloride, ethylacetate, diethyl ether, or toluene, can be employed for this purpose.The organic phase can be separated from the aqueous phase. Evaporationof the solvent from the organic phase provides the amine in the form ofa free base, which can generally be utilized without furtherpurification. Conversion of the tartaric acid salt to the correspondingfree base can be carried out at ambient temperatures.

The optical purity of the primary amine 3a or 3b expressed as % eeobtained by the asymmetric synthesis of this invention and resolutionwith the optically active derivative of tartaric acid will typically beat least about 70% ee. An optical purity of about 70% ee to about 80% eecan be attained without further purification by recrystallization. Thelevel of optical purity can be increased to about 96-99% ee by one ortwo recrystallization steps. Optimum enrichment levels can be achievedwith a minimum of experimentation.

The stereoselective synthesis of the alkylated oxindoles 2a and 2baccording to the present invention makes it possible to substantiallyincrease the chemical yield of the enantiomer of the primary amine 3a or3b of interest in the enrichment step. Specifically, enrichment of anenantiomeric mixture of the alkylated oxindoles in which one of thealkylated oxindoles predominates (as in the process of the invention)will result in a higher chemical yield of the primary amine of interestthan enrichment of a racemic mixture of the alkylated oxindoles, becauseof the higher concentration of the desired enantiomer in the startingmixture.

The concentrations of enantiomers in a reaction mixture obtained in thisinvention can be determined by (1) treating the primary amine with(-)-menthyl chloroformate, followed by HPLC analysis of thecorresponding diastereomeric carbamates; or (2) by treating the aminewith (+)-camphorsulfonyl chloride, followed by HPLC analysis of thecorresponding sulfonamide. The relative composition of a mixture ofenantiomers is given by the areas under the peaks corresponding to thediastereomers in HPLC chromatograms.

The absolute configuration of the enantiomer is assigned by convertingthe amines to known compounds whose absolute configurations have beenestablished. For example, the absolute configuration of the carbon atomat the 10-position of the primary amine can be determined by convertingthe tartaric acid salts of amines 3a or 3b into the correspondingoptically pure primary amine 3a or 3b by neutralization with diluteNaOH. The resulting optically pure primary amine can be reductivelycyclized in high yield by refluxing the amine in n-butanol in thepresence of excess sodium metal. The product can then be derivatizedwith (S)-(-)-α-methylbenzylisocyanate. The optical purity and absoluteconfiguration of the resulting product can be confirmed by HPLC analysisaccording to the method of Schonenberger and Brossi, Helv. Chim. Acta.,69:1486 (1986).

In an alternative embodiment, the crude enantiomeric mixture comprisingthe alkylated oxindoles 2a and 2b is subjected to a preferentialrecrystallization whereby a desired, optically pure, e.g. R-enantiomeror S-enantiomer, alkylated oxindole in high optical purity is separatedfrom the residual remaining racemate. The racemate is preferentiallyprecipitated leaving the optically pure oxindole in the filtrate.

A suitable recrystallization solvent is selected. Such solvent isselected from (1) a suitable protic solvent, such as an alcohol, e.g.methanol, ethanol, isopropanol, etc., (2) a suitable aprotic solvent,such as an aliphatic ether, e.g., tertiary-butyl methyl ether,isopropylethyl ether, etc. and (3) a suitable mixture of a protic andaprotic solvent.

The enantiomeric mixture comprising the alkylated oxindoles 2a and 2b istreated with the recrystallization solvent at a suitable temperature,typically at room temperature or slightly higher, e.g. 25°-30° C., for asufficient period of time to effect complete dissolution of the mixture.The resultant solution, comprising the dissolved mixture of 2a and 2band selected recrystallization solvent, is then allowed to cool to roomtemperature and/or allowed to remain at room temperature for a shortperiod of time, e.g. typically 5 to 10 minutes, whereupon a majoramount, typically 65 to 82%, of a first, pure enantiomer (either R or S)which is originally present in the mixture of 2a and 2b in an enrichedamount thereof, will remain in solution; and whereupon a residuecomprising a mixture of the other, second enantiomer and the remainderof the first enantiomer will precipitate out of solution as a solidmixture.

The resulting two phase mixture of pure enantiomer in solution andprecipitated solid is optionally, but preferably, cooled to atemperature of about 0° C. to about 5° C., e.g. by means of an ice bath,for a period of time to insure complete precipitation out of theresultant residue solid mixture of enantiomers.

As previously indicated, alkylation of the oxindole proceeds via astereoselective process and either one of the enantiomers of thealkylated oxindoles is obtained in excess, depending upon the choice ofcatalyst employed. Accordingly, either the R-enantiomer or theS-enantiomer can be present in the enantiomeric mixture of 2a and 2b inan enriched amount. It is this enriched enantiomer which is separatedfrom the precipitated solid mixture comprising at least the otherenantiomer.

The resulting two-phase mixture is then subject to a conventionalseparation, e.g. filtration, whereby the precipitated residue isseparated from the filtrate containing the first, optically pureenantiomer. The filtrate is then concentrated using conventional means,e.g. rotoevaporation, and the first, optically pure enantiomer isseparated, e.g. by filtration. The resulting first enantiomer is of highoptical purity.

The first enantiomer can then be treated further to form the amine, 3aor 3b, and thereafter to form eserethole or esermethole, usingconventional techniques well known in the art, e.g. Yu & Brossi,Heterocycles, 1988, Vol. 27, 1709, in either the R or S configuration.Employing the teachings of Lee et al., J. Org. Chem., 1991, Vol. 56,872, the eserthole can be converted to physostigmine and relatedcompounds.

In particular, the optically pure first enantiomer is reduced withhydrogen in acetic acid in the presence of platinum oxide. Amine 3a or3b is then treated with ethyl chloroformate in the presence oftriethylamine in toluene. Reductive cyclization using lithium aluminumhydride in tetrahydrofuran followed by chromotographic purificationprovided pure eserethole or esermethole of high optical purity.

The resultant eserethole or esermethole is reacted with fumaric acid ina conventional manner, e.g. typically at 45° to 50° C. for 0.5 to 1hours to form a fumarate salt which is recrystallized from methanol togive essentially 100% enantiomeric purity.

This invention will be more fully understood by reference to thefollowing examples in which all parts, proportions, ratios, andpercentages are by weight unless otherwise indicated.

Chiral Phase Transfer Alkylation Example 1 N-4-(Trifluoromethyl)benzyl!cinchoninium bromide

To a solution containing 0.48 g of (±)-5-methoxy-1,3 dimethyloxindole in20 ml of toluene was added, under nitrogen, 0.13 g (10 mole %) of N-4-(trifluoromethyl)benzyl!cinchoninium bromide (4-CF₃ -BCNB) followed by8 ml of 50% NaOH. After stirring the mixture for 10 minutes, a solutioncontaining 0.21 g of chloroacetonitrile in 20 ml of toluene was addeddropwise over 1 hour. After complete reaction, 25 ml of ice-cold waterwas added. The mixture was filtered through a small celite pad rinsingwith 10 ml of coluene. The filtrate was transferred to a separatoryfunnel, and the 2 layers were separated. The toluene extract wasconcentrated under reduced pressure and the residue was analyzed on aDaicel Chiralcel OD column eluting with a 10% isopropanol-hexanemixture. The enantiomeric excess of compound 2a in which R is methyl wasdetermined to be 72%.

Example 2 N- 3,4-(Dichloro)benzyl!cinchoninium Chloride As Catalyst

The procedure described in Example 1 was repeated with 0.12 of N-3,4-(dichloro-benzyl!cinchoninium chloride (3,4-Cl₂ -BCNC) in identicalfashion. The enantiomeric excess of compound 2a in which R is methyl wasfound to be 78% as determined by HPLC assay of the reaction mixture.

Example 3 N- 4-Bromobenzyl!cinchoninium Bromide As Catalyst

The procedure described in Example 1 was repeated with 0.14 g of N-4-bromobenzyl!cinchoninium bromide (4-Br-BCNB) in identical fashion. Theenantiomeric excess of compound 2a in which R is methyl was found to be68% as determined by HPLC assay of the reaction mixture.

Example 4 N- 3-Bromobenzyl!cinchoninium Bromide As Catalyst

The procedure described in Example 1 was repeated with 0.14 g of N-3-bromobenzyl!cinchoninium bromide (3-Br-BCNB) in identical fashion. Theenantiomeric excess of compound 2a in which R is methyl was found to be48% as determined by HPLC assay of the reaction mixture.

Example 5 N-Benzylquinidinium Bromide As Catalyst

The procedure described in Example 1 was repeated with 0.13 gN-benzylquinidinium bromide (BQNC) in identical fashion. Theenantiomeric excess of compounds 2a in which R is methyl was determinedto be 39% by HPLC assay of the reaction mixture.

Example 6 N- 3,4-Dichlorobenzyl!quinidinium Chloride As Catalyst

The procedure described in Example 1 was repeated with 0.20 g of N-3,4-dichlorobenzyl!quinidinium chloride (3,4-Cl₂ -BQNC) in identicalfashion. The enantiomeric excess of compound 2a in which R is methyl wasdetermined to be 77% by HPLC assay of the reaction mixture.

Example 7 N- 4-Trifluoromethyl)benzyl!dihydrocinchoninium Bromide AsCatalyst

The procedure described in Example 1 was repeated with 0.13 g of N-4-(trifluoromethyl)benzyl!dihydrocinchoninium bromide (4-CF₃ -H₂ -BCNB)in identical fashion. The enantiomeric excess of compound 2a in which Ris methyl was found to be 69% by HPLC assay.

Example 8 N- 4-Chlorobenzyl!cinchoninium Bromide As Catalyst

The procedure described in Example 1 was repeated with 0.13 g of N-4-chlorobenzyl!cinchoninium bromide (4-Cl-BCNB) in identical fashion.The enantiomeric excess of compound 2a in which R is methyl was found tobe 70% by HPLC assay of the reaction mixture.

Example 9 N- 3,4-(Dichloro)benzyl!cinchoninium Bromide As Catalyst

The procedure described in Example 1 was repeated with 0.12 g of 3,4-Cl₂-BCNB in identical fashion. The enantiomeric excess of compound 2a inwhich R is methyl was found to be 77% as determined by HLPC assay of thereaction mixture.

Example 10 Step (A): N- 3,4-(Dichloro)benzyl!cinchonium Chloride AsCatalyst

To a mixture containing 5.0 g of (±)-5-methoxy-1,3 dimethyloxindole and1.92 g of 3,4-Cl₂ -BCNC (15 mole %) in 200 ml of toluene was added underan efficient N₂ purge 40 ml of 50% NaOH. After stirring this mixture for10 min., a solution containing 2.17 g of choloracetonitrile in 20 ml oftoluene was added over 1 hour. After complete reaction, the mixture wascooled to 10°-15° C., and 160 ml of ice-cold H₂ O was added. Thereaction mixture was filtered through a Celite pad rinsing with 40 ml oftoluene. The combined filtrate was transferred to a separatory funnel,and the 2 layers were separated. The toluene solution was extracted with100 ml of cold 3N HCl, and 100 ml of cold H₂ O. After evaporation ofsolvent, 5.02 g (83%) of compound 2a in which R is methyl was isolatedas a slightly brownish oil. The entntiomeric excess of compound 2a wasdetermined to be 73% by HPLC.

Step (B): Catalytic Reduction of Nitriles to Primary Amines

The nitrile, 2a, obtained from Step (A) was taken up in 50 ml ofmethanol and 7.25 ml of concentrated hydrochloric acid. A sample of 0.5g of PtO₂ was added. The mixture was subjected to hydrogenation for 3hours at 45 psi. The catalyst was removed by filtration through filterpaper rinsing with 15 ml of methanol. The combined filtrate wasconcentrated under reduced pressure, and the residue was dissolved in100 ml of ice-cold water. The acidic aqueous solution was firstextracted with 50 ml of methylene chloride, and then basified with 5 mlof 50% NaOH. The basic aqueous chloride solution was extracted withmethylene chloride (3×50 ml). The combined organic extract was dried(Na₂ SO₄) and concentrated under reduced pressure giving 4.70 g (92%) ofthe corresponding amine, 3a.

Step (C): Enrichment of Amine by Selective Precipitation With ChiralTartaric Acid

The amine, 3a, from Step (B) was dissolved in 25 ml of acetonitrile. Asolution containing 6.42 g of dibenzoyl-D-tartaric acid in 25 ml ofacetonitrile was added rapidly under nitrogen. After stirring foranother 30 minutes, the precipitate that formed was filtered to give10.38 g of a white solid. The solid was recrystallized from 60 ml of 10%water-acetonitrile mixture giving 7.86 g (47.4%) of the tartrate salt ofthe amine; m.p. 136°-137° C. The optical purity was determined to be 99%by means of derivatization with (+)-camphorsulfonyl chloride followed byHPLC analysis of corresponding sulfonamide.

Example 11 N- 4-(Trifluoromethyl)benzyl!cinchonidinium Bromide AsCatalyst

Use of this catalyst gives predominantly the isomer leading to(+)-physostigmine.

To a stirred solution containing 1.19 g of1,3-dimethyl-5-methoxyoxindole and 0.83 g of chloroacetonitrile in 50 mlof toluene and 10 ml of 50% NaOH under nitrogen was added 0.53 g of theabove catalyst in 1 portion. After 30 min, the layers were separated.The toluene solution was washed with water, and then concentrated underreduced pressure to give the desired product in quantitative yield. Theenantiomeric excess (ee) of enantiomer 2b was determined to be 41% inthe following manner. The nitrile was reduced to the corresponding amineas described in Step (B) of Example 10, followed by derivatization ofthe amine with (-)-menthylchloroformate with HPLC analysis of theresultant carbamate on a Whatmann Partisil PXS 10/25 column eluting with10% acetonitrile/methylene chloride (2 ml/min; 254 mm detection).

Example 12 N- 3-(Trifluoromethyl)benzyl!cinchoninium Bromide As Catalyst

The procedure described in Example 1 was repeated with 0.13 g of N-3-(trifluoromethyl)benzyl!cinchoninium bromide (3-CF₃ -BCNB) inidentical fashion. The enantiomeric excess of compound 2a was found tobe 68% as determined by HPLC assay of the reaction mixture.

Example 13 N- 3,4-(Dichloro)benzyl!cinchoninium Chloride as Catalyst and(+)-5-Ethoxy-1,3-dimethyloxindole as Substrate

To a mixture containing 2.15 g of (±)-5-ethoxy-1,3-dimethyloxindole,also referred to as 1,3-dihydro-1,3-dimethyl-5-ethoxy-2H-indol-2-one and0.77 g of 3,4-Cl₂ -BCNB (15 mole %) in 80 ml of toluene was added underan efficient N₂ purge 16 ml of 50% NaOH. After stirring this mixture for10 min., a solution containing 0.87 g of chloroacetonitrile in 8 ml oftoluene was added over 1 hour. After complete reaction, 48 ml of icecold H₂ O was added. The reaction mixture was filtered through a Celitepad rinsing with 20 ml of toluene. The combined filtrate was transferredto a separatory funnel, and the two layers were separated. The toluenesolution was extracted with 20 ml of 2N HCl, and twice with 20 ml of H₂O. After evaporation of solvent, the slightly brownish oil was assayedon a Daicel Chiralcel OD column eluting with a 10% isopropanol-hexanesmixture. The enantiomeric excess of the compound 2a in which R is ethylwas determined to be 71%.

Example 14 N- 3,4-(Dichloro)benzyl!cinchoninium Chloride as Catalyst and(+)-5-Benzyloxy-1,3-dimethyloxindole as Substrate

The procedure described in Example 13 was repeated with 2.80 g of(±)-5-benzyloxy-1-1,3-dimethyloxindole, also referred to as5-benzyloxy-1,3-dihydro-1,3-dimethyl-2H-indol-2-one in identicalfashion. The enantiomeric excess of compound 2a in which R is benzyloxywas determined to be 73% by means of HPLC assay on a Daicel Chiralcel OJcolumn eluting with 40% isopropanol-hexanes.

The compound (±)-5-methoxy-1,3-dimethyl-oxindole employed in theExamples is also referred to as1,3-dihydro-1,3-dimethyl-5-methoxy-2H-indol-2-one.

Example 15

A. (3S)-1,3-Dimethyl-5-Ethoxyoxindolyl-3-Acetonitrile

To a 2 L 3-necked RB-flask fitted with a mechanical stirrer, N₂ -inlet,thermometer, condenser, and a rubber septum (threaded with apolyethylene rubing connected to a 50 mL syringe) was added 50 g of1,3-dimethyl-5-ethoxyoxindole, 2.49 g ofN-(3,4-dichlorobenzyl)cinchoninium chloride (2 mole %) and 625 mL oftoluene. This was followed by the addition of 125 mL of 50% NaOHsolution. The biphasic mixture was stirred for 15 minutes. To thismixture was then added a solution containing 20.33 g ofchloroacetonitrile (1.1 equivalents) in 31 mL of toluene via a syringepump. After complete reaction, the biphasic mixture was cooled to about10° C., and 500 mL of ice cold H₂ O was slowly added. The reactionmixture was filtered through Celite. The reaction flask and the Celitepad was rinsed with 300 mL of toluene. The 2 phases were separated. Theaqueous phase was extracted once with 300 mL toluene. The combinedtoluene solutions were extracted twice with 150 mL portions of 3N HCl,once with H₂ O (300 mL) and once with a saturated NaCl solution (300mL). The toluene solution was concentrated under reduced pressure togive 68.0 g (>100%) of 1,3-dimethyl-5-ethoxyoxindolyl-3-acetonitrile(S/R 87/13 by chiral hplc) as a solid. The above solid residue wasdissolved in 177 mL of hot methanol. The clear solution was cooled toroom temperature and then at 0°-5° C. for 30-40 minutes. Theprecipitated solid was filtered and washed with 20 ml of cold methanol,air dried to give 14.08 g (23.7%) of essentially pure racemic1,3-dimethyl-5-ethoxyoxindolyl-3-acetonitrile as a solid. The filtratewas concentrated to give 44.45 g (74.7%) of highly pure(3S)-1,3-dimethyl-5-ethoxyoxindolyl-3-acetonitrile (S/R 99/1 by chiralhplc).

Examples 16-22

The procedure of Example 15 was repeated except that various5-substituted 1,3-dimethyl oxindoles were employed with variousrecrystallization solvents. The results of these syntheses are given inthe TABLE below.

                  TABLE                                                           ______________________________________                                        Recrystallization of 1,3-Dimethyl-5-alkoxyoxindolyl-3-acetonitrile             ##STR8##                                                                     Ex-                     Dilution.sup.a                                                                       Before.sup.b                                                                          After.sup.c                            ample R.sup.1  Solvent  (v/w)  % ee(R or S)                                                                          % ee(R or S)                           ______________________________________                                        16    Methoxy  iPr.sub.2 O                                                                            29     70(S)   78(S)                                  17    Methoxy  .sup.t BuOCH.sub.3                                                                     7      70(S)   75(S)                                  18    Methoxy  95 EtOH  5      70(S)   82(S)                                  19    Methoxy  MeOH     3      70(S)   82(S)                                  20    Ethoxy   .sup.t BuOCH.sub.3                                                                     23     73(S)   91(S)                                  21    Ethoxy   MeOH     9      73(S)   83(S)                                  22    Ethoxy   MeOH     4      74(S)   98(S)                                  23    Ethoxy   MeOH     9      52(R)   95(R)                                  ______________________________________                                         .sup.a based on the theoretical amount of pure enantiomer available           .sup.b % ee of the crude oxindole                                             .sup.c % ee of the filtrate                                              

Example 24 R-Eserethole Fumarate

A. R-Eserethole

To a solution containing 49.1 g of(3R)-1,3-dimethyl-5-ethoxyoxindolyl-3-acetonitrile (95% ee) in 246 mL ofacetic acid is added 2.46 (g) of platinum oxide. The mixture ishydrogenated for 7 h at 45 psi at room temperature. The reaction mixtureis filtered and the filtrate is concentrated under reduced pressure. Theresidue is partitioned between toluene and a dilute sodium hydroxidesolution. The toluene solution is concentrated to give 51.92 g of thecorresponding amine.

To a solution of 49.9 g of the above amine and 24.29 g of triethylaminein 500 mL of toluene at 0° C. is added, under nitrogen, 23.87 g of ethylchloroformate. After complete addition, the mixture is allowed to warmup to room temperature and stirred for 4 h. The reaction mixture iswashed with water and the toluene solution is dried over anhydroussodium sulfate. The filtrate is concentrated under reduced pressure togive 60.21 g of the corresponding carbamate.

To a solution of 42.07 g of the carbamate in 106 mL of tetrahydrofuranat 0° C., is added under nitrogen, 273 mL of a 1M solution of lithiumaluminum hydride in tetrahydrofuran. After the addition is complete, themixture is heated under reflux for 1.5 h. After a standard workup, theresidue is purified by chromatography on silica gel to give 17.58 g of(R)-eserethole (95% ee).

B. (R)-Eserethole Fumarate

To a solution containing 38 g of eserethole (R/S 97.5/2.5) in ethanol isadded a hot solution of 21.49 g of fumaric acid in ethanol. The warmmixture is allowed to cool to room temperature, and then cooled furtherin an ice-bath. The precipitate that formed is filtered to give 47.6 gof white crystals. This is re-crystallized again from 190 mL of methanolto give 37.8 g of the fumarate as white crystals. Chiral hplc assay ofthis material showed that it is 100% optically pure.

The process of this invention has a number of advantages. The processfor the stereoselective synthesis of enantiomers provides precursors ofphysostigmine and physostigmine-like compounds in high chemical yieldand purity. The availability of one enantiomer of a give structure inconsiderable predominance over other enantiomers makes it possible toenhance the results obtained when the enantiomers are subsequentiallyresolved. The techniques for carrying out the stereoselective synthesisdo not present any unusual difficulties. The reagents required for theprocess are readily available or can be easily prepared usingconventional techniques. This invention provides a practical, economicalprocess for the total synthesis of selected enantiomers of physostigmineand related compounds.

We claim:
 1. A process for the synthesis of essentially enantiomericallypure 3-aminoalkyloxidole, wherein the process comprises:(a) reacting ata temperature of about 15° C. to about 25° C. a racemic oxindole of theformula ##STR9## where R is methyl, with at least one equivalent ofchloroacetonitrile in a biphasic reaction mixture having an aqueousphase comprising sodium hydroxide as a deprotonation agent and a solventphase comprising toluene and a catalytic amount of a compound of theformula ##STR10## wherein n is 1 or 2; R₁ is vinyl, R₂ is hydrogen, Y is4-Br and X is Br; and R₁ is vinyl, R₂ is hydrogen, Y is 4-CF₃ and X isBr; or R₁ is vinyl, R₂ is hydrogen, Y is 3,4-dichloro and X is Cl; or R₁is vinyl, R₂ is hydrogen, Y is 3,4-dichloro and X is Br; or R₁ is ethyl,R₂ is hydrogen, Y is 4-CF₃ and X is Br; or R₁ is vinyl, R₂ is OCH₃, Y is3,4-dichloro and X is Br;to thereby form two enantiomers of theresulting alkylated oxindole, wherein one of said enantiomers is in anamount of about 68% to about 90% enantiomeric excess relative to theother enantiomer; (b) treating the mixture with a recrystallizationsolvent selected from alcohol, aliphatic ether and mixture thereof toselectively dissolve the excess of one of said enantiomer to form asolution containing essentially one of said enantiomer and to form aprecipitate containing a racemic mixture of one of said enantiomer andthe other enantiomer, then, separating said solution from saidprecipitate and recovering from the solution the optically pure one ofsaid enantiomer; (c) converting nitrile groups of the resultingalkylated oxindoles to corresponding said aminoalkyloxindole bycatalytic reduction in the presence of hydrogen gas to form a mixture ofenantiomers of primary amines; and (d) contacting the mixture ofenantiomers of the said aminoalkyloxindole with a chiral acid in anamount sufficient to preferentially precipitate a salt of the chiralacid and one of the enantiomers, and recovering the resultingprecipitate, wherein the chiral acid is selected from the groupconsisting of dibenzoyl-D-tartaric acid and ditoluoyl-D-tartaric acid.2. The process according to claim 1, wherein R₁ is vinyl, R₂ ishydrogen, Y is 4-Br and X is Br.
 3. The process according to claim 1,wherein R₁ is vinyl, R₂ is hydrogen, Y is 4-CF₃ and X is Br.
 4. Theprocess according to claim 1, wherein R₁ is vinyl, R₂ is hydrogen, Y is3,4-dichloro and X is Cl.
 5. The process according to claim 1, whereinR₁ is vinyl, R₂ is hydrogen, Y is 3,4-dichloro and X is Br.
 6. Theprocess according to claim 1, wherein R₁ is ethyl, R₂ is hydrogen, Y is4-CF₃ and X is Br.
 7. The process according to claim 1, wherein R₁ isvinyl, R₂ is OCH₃, Y is 3,4-dichloro and X is Br.
 8. The processaccording to claim 1, wherein the chiral acid is dibenzoyl-D-tartaricacid or ditoluoyl-D-tartaric acid.
 9. The process according to claim 8,wherein the ratio of the volume of solvent to the total weight ofenantiomers of the primary amines is about 8:1 to about 12:1.
 10. Theprocess according to claim 8, wherein the ratio of the volume of solventto the total weight of enantiomers of the primary amines is about 10:1.11. The process according to claim 9, wherein the solvent isacetonitrile.
 12. The process according to claim 11, wherein the chiralacid is employed in an amount of about 0.5 to about 1 equivalents ofacid per equivalent of enantiomers of primary amines.
 13. The processaccording to claim 1, wherein the primary amine is obtained in anoptical purity of at least about 70% ee.
 14. The process according toclaim 12, which further comprises basifying the resulting tartaric acidsalt to form the corresponding free base.
 15. The process according toclaim 14, wherein the tartaric acid salt is dissolved in water and theresulting solution is neutralized with an aqueous inorganic base. 16.The process according to claim 15, which further comprises extractingamine from the aqueous solution with an organic solvent and isolatingthe amine by evaporation of the solvent.
 17. The process according toclaim 16, wherein the solvent for extraction is selected from the groupconsisting of methylene chloride, ethyl acetate, diethyl ether andtoluene.
 18. The process according to claim 17, wherein the inorganicbase for neutralization is selected from the group consisting of sodiumhydroxide, potassium hydroxide, sodium carbonate and potassiumcarbonate.